2-Imino-1-(o-nitrophenyl)-imidazolidines are described in the Hungarian patent specification No. 164,034. The Hungarian patent specification No. 164,035 refers to the synthesis of 2-imino-1-(o-aminophenyl)-imidazolidine derivatives. 2-Imino-3-(unsubstituted phenyl)-thiazolidine and the light protective effect of the latter compound have been described by Hino, T. et al. [Chem. Pharm. Bull. (Tokyo) 14 (11), 1201-1209 (1966)].
In particular, the invention relates to novel iminothiazolidine derivatives of the formula (I). ##STR2## wherein R.sup.1 and R.sup.2 represent, independently from each other, hydrogen or a lower alkyl group,
R.sup.3 is nitro or amino group, PA0 R stands for halo, lower alkyl, haloalkyl, nitro, amino, hydroxy, lower alkoxy, carboxy or lower alkoxycarbonyl, and PA0 n is 0, 1 or 2, PA0 3-(2-amino-4-chlorophenyl)-2-iminothiazolidine, PA0 3-(2-amino-4-chlorophenyl)-2-imino-5-methylthiazolidine, PA0 3-(2-amino-4-methylphenyl)-2-iminothiazolidine, PA0 1=3-(2-amino-4-chlorophenyl)-2-iminothiazolidine dihydrochloride PA0 2=3-(2-amino-5-chlorophenyl)-2-iminothiazolidine dihydrochloride PA0 3=3-(2-amino-4-chlorophenyl)-2-imino-4-methylthiazolidine dihydrochloride PA0 4=3-(2-amino-4-trifluoromethylphenyl)-2-iminothiazolidine hydrochloride PA0 5=3-(4-chloro-2-nitrophenyl)-2-iminothiazolidine hydrochloride PA0 6=3-(2-nitro-4-trifluoromethylphenyl)-2-iminothiazolidine hydrochloride PA0 7=3-(2-amino-4-methoxyphenyl)-2-iminothiazolidine dihydrochloride PA0 8=3-(2-amino-4-chlorophenyl)-2-iminothiazolidine di(ethanesulfonate) PA0 9=3-(5-chloro-2-nitrophenyl)-2-iminothiazolidine PA0 10=3-(2-nitrophenyl)-2-iminothiazolidine PA0 11=3-(4-methoxy-2-nitrophenyl)-2-iminothiazolidine hydrobromide PA0 12=3-(2-amino-4-chlorophenyl)-2-imino-5-methylthiazolidine ethanesulfonate PA0 13=3-(2-amino-4-methylphenyl)-2-iminothiazolidine PA0 14=3-(4-aminophenyl)-2-imino-1,3-thiazolidine PA0 15=3-(4-amino-2-nitrophenyl)-2-iminothiazolidine
and the pharmaceutically acceptable acid addition salts thereof.
In the specification a lower alkyl group is a linear or branch chained alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isobutyl, etc. Halo means fluoro, chloro, bromo or iodo atoms. Haloalkyl comprises mono-, di- or trihaloalkyl groups, such as chloromethyl, bromomethyl, chloroethyl, dichloromethyl and especially trifluoromethyl. A lower alkoxy group is a linear or branch chained alkoxy having 1 to 4 carbon atoms, e.g. methoxy, ethoxy, n-propoxy, isobutoxy, etc. A lower alkoxycarbonyl group is, for example, methoxy- or ethoxycarbonyl, and can have 1 to 4 carbon atoms in the alkoxy chain.
The pharmaceutically acceptble acid addition salts of the iminothiazolidine derivatives of the formula (I) can be inorganic or organic acid addition salts, such as hydrochloride, hydrobromide, sulfate, nitrate, acetate, lactate, fumarate, maleate, tartrate, methanesulfonate, ethanesulfonate, etc.
A subclass of the compounds of the invention consists of the nitro compounds of the formula (Ia) ##STR3## wherein R.sup.1, R.sup.2, R and n are as stated above, and the pharmaceutically acceptable acid addition salts thereof.
Preferred representatives of the nitro compounds of the formula (Ia) are derivatives in which the nitro group is in position 2 relative to the phenyl carbon atom bound to the thiazolidine nucleus.
Preferably, in formula (Ia) R.sup.1 and R.sup.2 are hydrogen, n is 0 or 1 and R represents chloro, trifluoromethyl, methoxy or amino group.
A further subclass of the compounds of the invention consists of the amino compounds of the formula (Ib) ##STR4## wherein R.sup.1, R.sup.2, R and n are as stated above, and the pharmaceutically acceptable acid addition salts thereof.
Preferred representatives of the amino compounds of the formula (Ib) are derivatives in which the amino group is in position 2 relative to the phenyl carbon atom bound to the thiazolidine nucleus.
Preferably, in formula (Ia), R.sup.1 and R.sup.2 stand for hydrogen or methyl, n is 0 or 1, and R represents a chloro, trifluoromethyl, methoxy or methyl group.
Especially preferred iminothiazolidine derivatives of the invention are:
and the pharmaceutically acceptable acid addition salts thereof.
The novel iminothiazolidine derivatives of the invention have valuable antidepressant, antiparkinsonic, antiepileptic and spasmolytic properties.
The invention comprises all enantiomers, diastereomers and racemates of the compounds of the formula (I).
Furthermore, the invention relates to a process for preparing iminothiazolidine derivatives of the formula (I) and the pharmaceutically acceptable acid addition salts thereof, in which
(a) for preparing compounds of the formula (I), wherein R.sup.3 is nitro, i.e. compounds of the formula (Ia)
(a.sub.1) an isothiocyanate of the formula (II) ##STR5## wherein R.sup.1, R.sup.2, R and n are as stated above, is cyclized in the presence of an acid; or
(a.sub.2) a compound of the formula (III) ##STR6## wherein R and n are as stated above, is reacted with a compound of the formula (IVa) or a tautomer of the formula (IVb) ##STR7## wherein R.sup.1 and R.sup.2 are as stated above; or
(a.sub.3) a compound of the formula (V) ##STR8## wherein R.sup.1, R.sup.2 and n are as stated above and Z is a leaving group, is reacted with thiourea, and the obtained compound of the formula (VI) ##STR9## is cyclized; or
(a.sub.4) a compound of the formula (VII) ##STR10## wherein R and n are as stated above, is reacted with an isothiocyanate of the formula (VIII) ##STR11## wherein R.sup.1 and R.sup.2 are as stated above, Z is a leaving group; or
(a.sub.5) a compound of the formula (IX) ##STR12## wherein R.sup.1, R.sup.2, R and n are as stated above, is nitrated; or
(a.sub.6) a disulfide of the formula (XI) ##STR13## wherein R.sup.1, R.sup.2, R and n are as stated above, is reacted with cyanogen bromide; or
(b) for preparing compounds of the formula (I), wherein R.sup.3 is amino, i.e. compounds of the formula (Ib)
(b.sub.1) a compound of the formula (Ia), wherein R.sup.1, R.sup.2, R and n are as stated above, is reduced; or
B.sub.2) an isothiocyanate of the formula (II), wherein R.sup.1, R.sup.2, R and n are as stated above, is reduced, and the reaction product obtained is cyclized in the presence of an acid; or
(b.sub.3) an isothiuronium salt of the formula (VI), wherein R.sup.1, R.sup.2, R and n are as stated above, Z is a leaving ion, is reduced and the reaction product obtained is cyclized; or
(b.sub.4) the amino group of a compound of the formula (VII), wherein R and n are as stated above, is protected, the obtained compound of the formula (X) ##STR14## wherein R and n are as stated above, W is a protecting group, is reduced, the reaction product obtained is reacted with an isothiocyanate of the formula (VIII), wherein R.sup.1 and R.sup.2 are as stated above, Z is a leaving group, and finally the protecting group W is removed;
and, if desired, an obtained compound of the formula (I) is converted to a pharmaceutically acceptable acid addition salt.
In accordance with method a.sub.1 of the invention, an isothiocyanate of the formula (II) is cyclized in the presence of an acid. Preferably, the cyclization is performed in a protic dipolar solvent, such as methanol or ethanol, at an elevated temperature, preferably at 60.degree. to 100.degree. C., for example at the boiling point of the reaction mixture. The acid used is preferably hydrogen chloride, also in the gaseous state. Other acids can also be employed. The product formed can be isolated from the mixture by conventional methods, e.g. cooling the mixture, evaporating the solvent or adding a solvent such as ether. Suitably, the product is isolated in the form of a crystalline salt.
According to method a.sub.2 of the invention, a compound of the formula (III) is reacted with a compound of the formula (IVa) or a tautomeric form thereof represented by the formula (IVb). The reaction is suitably performed in an aprotic dipolar solvent such as dimethyl sulfoxide, dimethyl formamide, hexamethyl phosphoric triamide. In general, the reaction temperature does not exceed 100.degree. C. The reaction mixture is heated until no starting compound of the formula (III) is present, then the reaction product is isolated by conventional method. For example, the reaction mixture is diluted with water and the product is extracted with a solvent immiscible with water, such as dichloromethane. Then, the solvent is removed and the product is separated in the form of the free base or as a crystalline acid addition salt, e.g. hydrochloride, hydrobromide, etc.
According to method a.sub.3 of the invention, a compound of the formula (V) is reacted with thiourea in a protic dipolar solvent, preferably methanol or ethanol, at an elevated temperature, suitably at a temperature of 60.degree. to 100.degree. C., preferably at the boiling point of the reaction mixture. The reaction proceeds in several hours. When the starting compound of the formula (V) is no longer present, the solvent is removed, and the residue consisting of the compound of the formula (VI) is cyclized. It is preferred to perform the cyclization reaction by heating the compound of the formula (VI) with an acid, suitably acetic acid. Preferred starting substances are compounds of the formula (V), wherein Z represents a halo, such as chloro or bromo atom, or a lower alkylsulfonyloxy, e.g. mesyloxy, or an arylsulfonyloxy, e.g. p-toluenesulfonyloxy group.
In accordance with a method a.sub.4 of the invention, the compounds of the formulae (VII) and (VIII) are reacted in an organic solvent having preferably a high boiling point, such as butanol, or in melt, without any solvent. The reaction temperature is, in general, about 100.degree. to 150.degree. C. It is preferred to perform the reaction at the reflux temperature. The product formed can be separated in the form of crystalline acid addition salts. Preferred starting substances are compounds of the formula (VIII), wherein Z stands for halo, e.g. chloro or bromo.
According to method a.sub.5 of the invention, the nitration is performed suitably with nitric acid. The starting compound of the formula (IX) is dissolved in a suitable solvent, for example halogenated hydrocarbon, such as chloroform, and reacted with nitric acid at a temperature of 0.degree. to 20.degree. C. The nitro derivative obtained is isolated in a conventional manner: the excess of the nitric acid is removed suitably by treatment with cold water, the solvent is evaporated and the residual product is crystallized from a solvent.
According to method a.sub.6 of the invention, a disulfide of the formula (XI) is reacted with cyanogen bromide in an inert organic solvent, preferably an ether, such as diethyl ether, tetrahydrofuran, dioxane, etc., with heating, suitably at the boiling point of the solvent. Preferably, the cyanogen bromide is employed in excess.
According to method b.sub.1 of the invention, a compound of the formula (Ia) is reduced, suitably by catalytic hydrogenation. The hydrogenation is performed in a suitable solvent, for example lower alkanol such as methanol or ethanol, in the presence of a noble metal catalyst, preferably palladium. Catalysts applied to a carrier can be used. The hydrogenation reaction proceeds preferably at a pressure of 1 to 5 atm and at an elevated temperature or at room temperature. It is preferred to hydrogenate the compound of the formula (Ia) at room temperature and at atmospheric pressure. The product is separated in a conventional manner. Suitably, the catalyst is removed by filtration, the filtrate is evaporated or an excess of acid is added to obtain an acid addition salt of the product at a low temperature, e.g. about 0.degree. C. Thus, the product is isolated in the form of either the free base or a crystalline acid addition salt.
In accordance with method b.sub.2 of the invention, the starting compound of the formula (II) is reduced, preferably by catalytic hydrogenation. Preferred catalysts are noble metal catalysts, such as palladium, suitably applied to a carrier, e.g. charcoal. In general, the hydrogenation is performed in a suitable organic solvent, preferably a lower alkanol, such as methanol or ethanol, at a pressure of 1 to 5 atm and at room temperature or somewhat elevated temperatures. It is preferred to hydrogenate at room temperature and at atmospheric pressure. At the end of the reaction, the catalyst is removed by filtration, and the filtrate is treated with an excess of an acid, preferably hydrochloric acid or ethanesulfonic acid. The cyclization is carried out at lower temperatures, suitably at about 0.degree. C. In general, the reaction time amounts to several hours. The product formed can be separated in the form of a crystalline acid addition salt. It is also possible to perform the hydrogenation of the compound of the formula (II) and the cyclization of the reduction product in a single step.
According to method b.sub.3 of the invention, an isothiuronium salt of the formula (VI) is reduced, preferably by catalytic hydrogenation in the presence of a catalyst, such as a noble metal catalyst, preferably palladium which can be applied to a carrier, e.g. charcoal. The hydrogenation can be performed in a suitable solvent, for example lower alkanol, such as methanol or ethanol, or water, at a pressure of 1 to 5 atm and at room temperature or under heating. It is preferred to hydrogenate at room temperature and at atmospheric pressure. At the end of the reduction, the catalyst is removed by filtration, and the filtrate is heated at the boiling point of the solvent. The reduction and cyclization can be performed in a single step, too.
According to method b.sub.4 of the invention, the amino group of the nitro compound of the formula (VII) is protected by means of a suitable protecting group, e.g. a lower alkoxycarbonyl, preferably tert.-butoxycarbonyl group. For example, the tert.-butoxycarbonyl group is introduced by reacting the compound of the formula (VII) with tert.-butylazido formiate in a neutral solvent, such as dioxane or tetrahydrofuran, in the presence of a base, such as triethyl amine, at room temperature. Then, the nitro group of the compound of the formula (X) is reduced, preferably by catalytic hydrogenation in the presence of a noble metal catalyst, e.g. palladium which can be applied to a carrier, such as charcoal. The hydrogenation is suitably performed at a pressure of about 1 to 5 atm and at room temperature or somewhat elevated temperatures. It is preferred to hydrogenate at room temperature and atmospheric pressure. At the end of the reduction the catalyst is removed by filtration, the filtrate is evaporated, and the residual product is reacted with a compound of the formula (VIII). The latter reaction can be carried out at higher temperatures, for example about 100.degree. to 150.degree. C., in a solvent or without any solvent. Suitable solvents for this purpose are organic solvents having high boiling point, such as butanol. The reaction proceeds in several hours. Then, the protecting group W is removed by conventional methods. For example, the alkoxycarbonyl protecting group is split off by treatment with aqueous hydrochloric acid, a solution of hydrogen chloride in an alcohol or with trifluoroacetic acid at room temperature or under heating. The above reaction sequence can also be performed in a single step.
The obtained compounds of the formula (I) can be reacted with inorganic or organic acids to give the corresponding acid addition salts. Similarly, the free base can be liberated from the acid addition salt by reacting the former with a base. These reactions can be carried out by conventional methods. For example, a compound of the formula (I) is reacted in a suitable inert solvent with a stoichiometric amount or a slight excess of an acid to obtain the acid addition salt thereof.
The starting compounds employed in the process of the invention are known or can be prepared in a manner known per se. The preparation of the starting substances is shown in the Examples in detail.
The starting compounds of the formula (XI) can be prepared by either reacting a compound of the formula (XIII) ##STR15## wherein R.sup.1 and R.sup.2 are as stated above, with a nitro derivative of the formula (XII) ##STR16## wherein R and n are as stated above, X represents halo, preferably chloro, or treating a compound of the formula (II) with an alkali metal alkoxide.
The novel compounds of the formula (I) possess valuable antidepressant, antiparkinsonic, antiepileptic and spasmolytic properties accompanied by a moderate analgesic activity. The activity of the compounds of the invention are examined by the following tests.